BACKGROUND Peripheral artery disease (PAD), a diffuse manifestation of atherothrombosis, is a major cardiovascular threat. Although platelets are primary mediators of atherothrombosis, their role in the pathogenesis of PAD remains unclear. OBJECTIVES The authors sought to investigate the role of platelets in a cohort of symptomatic PAD. METHODS The authors profiled platelet activity, mRNA, and effector roles in patients with symptomatic PAD and in healthy controls. Patients with PAD and carotid artery stenosis were recruited into ongoing studies (NCT02106429 and NCT01897103) investigating platelet activity, platelet RNA, and cardiovascular disease. RESULTS Platelet RNA sequence profiling mapped a robust up-regulation of myeloid-related protein (MRP)-14 mRNA, a potent calcium binding protein heterodimer, in PAD. Circulating activated platelets were enriched with MRP-14 protein, which augmented the expression of the adhesion mediator, P-selectin, thereby promoting monocyte-platelet aggregates. Electron microscopy confirmed the firm interaction of platelets with monocytes in vitro and colocalization of macrophages with MRP-14 confirmed their cross talk in atherosclerotic manifestations of PAD in vivo. Platelet-derived MRP-14 was channeled to monocytes, thereby fueling their expression of key PAD lesional hallmarks and increasing their directed locomotion, which were both suppressed in the presence of antibody-mediated blockade. Circulating MRP-14 was heightened in the setting of PAD, significantly correlated with PAD severity, and was associated with incident limb events. CONCLUSIONS The authors identified a heightened platelet activity profile and unraveled a novel immunomodulatory effector role of platelet-derived MRP-14 in reprograming monocyte activation in symptomatic PAD. (Platelet Activity in Vascular Surgery and Cardiovascular Events [PACE]; NCT02106429; and Platelet Activity in Vascular Surgery for Thrombosis and Bleeding [PIVOTAL]; NCT01897103).

中文翻译：

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血小板衍生的 MRP-14 诱导有症状的外周动脉疾病患者的单核细胞活化

背景外周动脉疾病（PAD）是动脉粥样硬化血栓形成的一种弥漫性表现，是一种主要的心血管威胁。尽管血小板是动脉粥样硬化血栓形成的主要介质，但它们在 PAD 发病机制中的作用仍不清楚。目的 作者试图调查血小板在一组有症状的 PAD 中的作用。方法作者分析了有症状的 PAD 患者和健康对照的血小板活性、mRNA 和效应子作用。患有 PAD 和颈动脉狭窄的患者被招募到正在进行的研究（NCT02106429 和 NCT01897103）中，研究血小板活性、血小板 RNA 和心血管疾病。结果 血小板 RNA 序列分析绘制了 PAD 中髓样相关蛋白 (MRP)-14 mRNA（一种有效的钙结合蛋白异二聚体）的稳健上调。循环活化的血小板富含 MRP-14 蛋白，它增加了粘附介质 P-选择素的表达，从而促进了单核细胞-血小板聚集。电子显微镜证实了血小板与体外单核细胞的牢固相互作用，巨噬细胞与 MRP-14 的共定位证实了它们在体内 PAD 的动脉粥样硬化表现中的串扰。血小板衍生的 MRP-14 被引导至单核细胞，从而促进其关键 PAD 病变标志的表达并增加其定向运动，这两者在存在抗体介导的阻断时均被抑制。循环 MRP-14 在 PAD 环境中升高，与 PAD 严重程度显着相关，并与肢体事件相关。结论作者确定了血小板活性增强的特征，并阐明了血小板衍生的 MRP-14 在重编程有症状 PAD 单核细胞活化中的新型免疫调节效应作用。（血管外科和心血管事件中的血小板活性 [PACE]；NCT02106429；以及血栓形成和出血的血管外科中的血小板活性 [PIVOTAL]；NCT01897103）。